Indazolamides with analgesic activity

ABSTRACT

An indazolamide (I), wherein X, R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings given in the description, and addition salts thereof with a pharmaceutically acceptable acid, a method for the preparation thereof and a pharmaceutical composition containing the same.

The present invention relates to indazolamides endowed with analgesicactivity, to a method for the preparation thereof and to apharmaceutical composition containing the same.

Chronic pain is very widespread. On average, about 20% of the adultpopulation suffers from this. This type of pain is generally associatedwith chronic lesions and/or degenerative processes. Typical examples ofpathologies characterized by chronic pain are rheumatoid arthritis,osteoarthritis, fibromyalgia, neuropathies, etc. [Ashburn M A, Staats PS, Management of chronic pain. Lancet 1999; 353: 1865-69].

The analgesic drugs currently used belong essentially to two classes:non-steroidal anti-inflammatories (NSAIDs), which combine the analgesicactivity with anti-inflammatory activity, and opioid analgesics. Theseclasses constitute the bases for the “analgesic scale” with threegrades, proposed by the World Health Organisation for thepharmacological treatment of pain [Textbook of pain. Fourth edition. P.D. Wall and R. Meizack Eds. Churchill Livingstone, 1999].

Chronic pain is often debilitating and causes loss of ability to workand poor quality of life. It therefore has consequences in terms of botheconomic and social impacts. In addition, there is a significant numberof patients whose pain condition still does not have a suitabletreatment [Scholz J, Woolf C J. Can we conquer pain? Nat Neurosci.November 2002;5 Suppl: 1062-7].

The extensive research efforts devoted towards identifying a suitableanalgesic compound have not yet led to appreciable results.

It has now been found, surprisingly, that a novel family ofindazolamides has these properties.

In a first aspect, the present invention thus relates to an indazolamideof formula I:

wherein

-   X is an NHC(O) or C(O)NH group,-   R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino,    sulphonylmethyl, aminosulphonylmethyl, linear or branched C₁₋₃ alkyl    or C₁₋₃ alkoxy group,-   R2 is a hydrogen atom or a linear or branched C₁₋₆ alkyl group or an    aryl(C₁₋₃)alkyl group in which the abovementioned groups are    optionally substituted with one or more substituents chosen from the    group comprising halogen atoms, C₁₋₃ alkyl and C₁₋₃ alkoxy,-   R3 and R4, which may be identical or different, are a hydrogen or    halogen atom, or an amino, nitro, hydroxyl, linear or branched C₁₋₃    alkyl, C₁₋₃ alkoxy, di(C₁₋₃)alkylamino, acetylamino or    O—(C₁₋₃)alkylphenyl group, or R3 and R4, together, form a 5- to    7-membered ring in which one or two of the said members may be a    hetero atom chosen from N, S and O,-   R5, R6, R7 and R8, which may be identical or different, are H or    methyl;    and the acid-addition salts thereof with pharmaceutically acceptable    organic and mineral acids.

Preferred meanings of R1 are H, methyl and methoxy.

Preferred meanings of R2 are H, methyl and isopropyl.

Preferred meanings of R3 are H, methyl, hydroxyl, amino anddimethylamino.

Preferred meanings of R4 are H, methyl and hydroxyl.

A preferred meaning of R5, R6, R7 and R8 is H.

The analgesic activity of the compounds of formula (I) was demonstratedby means of two experimental models in rats: mechanic hyperalgesiainduced by CFA and mechanical hyperalgesia in diabetic neuropathyinduced by streptozotocin.

As is known in the prior art, the abovementioned experimental models maybe considered as predictive of the activity in man.

CFA-induced hyperalgesia represents a syndrome characterized by theactivation of circuits devoted to controlling the inflammatory responseand associated with the appearance of conditions that interfere with theperception of pain. Specifically, the injection of CFA is capable ofinducing peripherally the release of the “inflammatory soup” (mediatorsof the inflammatory response and algogenic agents) responsible for thelocal injury, and centrally, in the spinal cord, biochemical changesthat sustain the amplification of the perception of pain. As is wellknown, this model constitutes a valid tool for studying drugs for use inthe treatment of inflammatory pain in man and, in particular, incontrolling conditions such as hyperalgesia and allodynia.

Typical examples of human pathologies characterized by this type of painassociated with degenerative inflammatory processes are rheumatoidarthritis and osteoarthritis.

For its part, diabetic neuropathy induced by streptozotocin in ratsrepresents an insulin-dependent syndrome characterized by a concomitantreduction in the speed of conduction of the motor and sensory nerves andthe appearance of a series of abnormalities in the perception of pain.As is well known, this experimental model constitutes a useful tool forstudying drugs for use in the treatment of neuropathic pain in man. Inparticular, the model represents a valid example of a large group oftypes of neuropathic pain characterized by phenomena such ashyperalgesia and allodynia consequent to primary lesions or dysfunctionsof the nervous system. Typical examples of human pathologiescharacterized by dysfunctions of this type and by the presence ofneuropathic pain are diabetes, cancer, immunodeficiency, trauma,ischemia, multiple sclerosis, sciatica, neuralgia of the trigeminalnerve and post-herpetic syndromes.

In a second aspect, the present invention relates to a process forpreparing the compounds of formula (I) and the acid-addition saltsthereof with pharmaceutically acceptable organic and mineral acids,characterized in that it comprises the following stages:

-   a) condensing an amine of the formula (II)

-    in which    -   X, R3, R4, R5, R6, R7 and R8 have the meanings given above, with        an indazolecarboxylic acid derivative of formula (IIIa)

-   -    in which    -   R1 and R2 have the meanings given above, and    -   Y is a Cl or Br atom, or a group OR or OC(O)R, in which R is an        alkyl with a linear or branched chain containing from 1 to 6        carbon atoms,    -   or of formula (IIIb)

-   -    in which    -   R1 has the meanings given above, to give the indazolamide of        formula (I), and

-   b) optionally, forming an acid-addition salt of the indazolamide of    formula (I) with a pharmaceutically acceptable organic or mineral    acid.

The amine of formula (II) may be obtained according to conventionalmethods, for example by alkylation of isonipecotamide with a suitablehalide, followed by reduction of the amide to a primary amine (WO98/07728) or by protecting the aminomethylpiperidine with benzaldehyde(Synthetic Communications 22(16), 2357-2360, 1992), alkylation with asuitable halide and deprotection.

The intermediate of formula (II) in which X, R3, R4, R5, R6, R7 and R8have the meanings given above is novel.

In a third aspect, the present invention thus relates to an intermediateof formula (II) in which X, R3, R4, R5, R6, R7 and R8 have the meaningsgiven above.

The indazoles of formulae (IIIa) and (IIIb) may also be obtainedaccording to conventional methods. For example, the compounds of formula(IIIa) in which Y is chlorine may be obtained with thionyl chloride fromthe corresponding acid (J. Med. Chem, 1976, Vol. 19 (6), pp. 778-783),while the compounds of formula (IIIa) in which Y is OR or OC(O)R may beobtained by known esterification reactions or known reactions forforming mixed anhydrides (R. C. Larock, Comprehensive OrganicTransformations, VCH, pp. 965-966). In turn, the compounds of formula(IIIb) may be obtained according to J.O.C. 1958, Vol. 23 p. 621.

In one embodiment of the process of the present invention, stage (a) isperformed by reacting a compound of formula (II) with a compound offormula (IIIa) in which Y is chlorine with a compound of formula (IIIb)in the presence of a suitable diluent and at a temperature in the rangebetween 0 and 140° C. for a time in the range between 0.5 and 20 hours.

Preferably, the reaction temperature is in the range between 15 and 40°C. Advantageously, the reaction time ranges from 1 to 14 hours.

Preferably, the diluent is aprotic, polar or apolar. Even morepreferably, it is an aprotic apolar diluent. Examples of suitableaprotic apolar diluents are aromatic hydrocarbons, for instance toluene.Examples of suitable aprotic polar diluents are dimethylformamide anddichloromethane.

In the embodiment in which a compound of formula (IIa) is used, in whichY is Cl or Br, the abovementioned stage (a) may be performed in thepresence of an organic or mineral acid acceptor.

Examples of suitable organic acid acceptors are pyridine, triethylamineand the like. Examples of suitable mineral acid acceptors are alkalimetal carbonates and bicarbonates.

According to the process of the present invention, in stage (b), theaddition of a pharmaceutically acceptable organic or mineral acid to anindazolamide of formula (I), obtained in stage a) is preferably precededby a stage of isolating the said indazolamide.

Typical examples of pharmaceutically acceptable acids are: oxalic acid,maleic acid, methanesulphonic acid, para-toluenesulphonic acid, succinicacid, citric acid, tartaric acid, lactic acid, hydrochloric acid,phosphoric acid, sulphuric acid.

In a fourth aspect, the present invention relates to a pharmaceuticalcomposition containing an effective amount of a compound of formula (I),or an addition salt thereof with a pharmaceutically acceptable acid, andat least one pharmaceutically acceptable inert ingredient.

A typical example of a pathological condition that may be usefullytreated with a pharmaceutical composition according to the presentinvention is chronic pain. Typically, this chronic pain is referable tochronic lesions or to degenerative processes, for example rheumatoidarthritis, osteoarthritis, fibromyalgia, oncology pain, neuropathic painand the like.

Preferably, the pharmaceutical compositions of the present invention areprepared in the form of suitable dosage forms.

Examples of suitable dosage forms are tablets, capsules, coated tablets,granules, solutions and syrups for oral administration; creams,ointments and medicated patches for topical administration;suppositories for rectal administration and sterile solutions forinjectable, aerosol or ophthalmic administration.

Advantageously, these dosage forms will be formulated so as to ensure acontrolled release over time of the compound of formula (I) or of a saltthereof with a pharmaceutically acceptable acid. Specifically, dependingon the type of treatment, the required release time may be very short,normal or sustained.

The dosage forms may also contain other conventional ingredients, suchas: preserving agents, stabilizers, surfactants, buffers, salts forregulating the osmotic pressure, emulsifiers, sweeteners, colorants,flavourings and the like.

In addition, when required for particular treatments, the pharmaceuticalcomposition of the present invention may contain other pharmacologicallyactive ingredients whose simultaneous administration is useful.

The amount of compound of formula (I) or of a salt thereof with apharmaceutically acceptable acid in the pharmaceutical composition ofthe present invention may vary within a wide range depending on knownfactors, for instance the type of disease to be treated, the seriousnessof the disease, the patient's body weight, the dosage form, the selectedroute of administration, the number of daily administrations and theefficacy of the selected compound of formula (I). However, the optimumamount may be readily and routinely determined by a person skilled inthe art.

Typically, the amount of compound of formula (I) or of a salt thereofwith a pharmaceutically acceptable acid in the pharmaceuticalcomposition of the present invention will be such as to ensure a levelof administration of between 0.001 and 100 mg/kg/day. Even morepreferably, the amount will be between 0.1 and 10 mg/kg/day.

The dosage forms of the pharmaceutical composition of the presentinvention may be prepared according to techniques that are well known topharmaceutical chemists, including mixing, granulation, tabletting,dissolution, sterilization and the like.

The examples that follow serve to illustrate the invention without,however, limiting it.

In the examples that follow, the substituents on the aromatic ring (R3and R4) are indicated with the numbering in bold.

EXAMPLE 1 2-(4-(aminomethyl)-1-piperidyl)-N-phenylacetamidedihydrochloride (AF3R279) (Compound II: R3=R4=R5=R6=R7=R8=H, X═C(O)NH)

-   a) N-hexahydro-4-pyridylmethyl-N-phenylmethylideneamine

Benzaldehyde (12.7 g; 0.12 mol) was added dropwise to a solution of4-aminomethylpiperidine (13.7 g; 0.12 mol) in toluene (50 ml).

The solution thus obtained was stirred at room temperature. After 3hours, the solvent was removed by evaporation under reduced pressure andthe residue was taken up twice with toluene (2×50 ml).

N-Hexahydro4-pyridylmethyl-N-phenylmethylidineamine (25 g) was thusobtained, and was used without further purification.

-   b) 2-(4-(aminomethyl)-1-piperidyl)-N-phenylacetamide

The product prepared as described in stage a) above (26.3 g; 0.13 mol)was dissolved in absolute ethanol (100 ml) and added to a suspensioncontaining N-2-chloroacetylaniline (22.4 g; 0.13 mol), prepared asdescribed in Beilstein (I) Syst. No 1607, p. 243, and anhydrouspotassium carbonate (33 g; 0.24 mol) in absolute ethanol (250 ml).

The suspension thus obtained was refluxed for 16 hours. The reactionmixture was allowed to cool to room temperature and filtered. Thefiltrate was evaporated under reduced pressure and the residue thusobtained was suspended in 3N HCl (90 ml) and stirred at room temperaturefor 2 hours.

The solution was transferred into a separating funnel and the acidicaqueous phase was washed 4 times with ethyl acetate (4×50 ml). Theaqueous phase was basified to pH 13 with 6N NaOH and extracted withdichloromethane (80 ml). The organic phase was dried over Na₂SO₄ and thesolvent was removed by evaporation under reduced pressure to give2-(4-(aminomethyl)-1-piperidyl)-N-phenylacetamide (10 g).

-   c) 2-(4-(aminomethyl)-1-piperidyl)-N-phenylacetamide dihydrochloride

The product prepared as described in stage b) above (4 g) was convertedinto the corresponding dihydrochloride by dissolving in ethanol (60 ml),adding hydrochloric ethanol (5 ml) and crystallizing from 95° ethanol.

2-(4-(Aminomethyl)-1-piperidyl)-N-phenylacetamide dihydrochloride (3.5g) was thus obtained.

m.p.: 288° C. (dec.)

Elemental analysis

For C₁₄H₂₁N₃O.2HCl.H₂O

C H N Found % 49.73 7.55 12.21 Calculated % 49.71 7.45 12.42

¹H-NMR (δ, DMSO-d₆): 1.44-1.70 (m, 2H); 1.71-2.20 (m, 3H); 2.77 (s, 2H);3.04-3.26 (m, 4H); 4.18 (s, 2H); 7.12 (t, J=7 Hz, 1H); 7.35 (t, J=7 Hz,2H); 7.66 (d, J=7 Hz, 2H); 8.33 (broad s, 3H); 10.18 (s 1H); 11.07 (s,1H).

EXAMPLE 2N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamidehydrochloride (AF3R172) (Compound I: R1=R3=R4=R5=R6=R7=R8=H, R2=i-C₃H₇,X═C(O)NH)

1-(1-Methylethyl)-1H-indazole-3-carboxyl chloride (17.5 g; 0.079 mol)prepared as described in EP-A-0 975 623 was added portionwise to asuspension of the product prepared as described in Example 1b) (19.5 g;0.079 mol) in toluene (300 ml).

The reaction mixture was stirred at room temperature for 6 hours. Thesolvent was then removed by evaporation under reduced pressure. Theresidue was taken up in 1N NaOH (100 ml) and dichloromethane (100 ml)and transferred into a separating funnel.

The organic phase was separated out and dried over Na₂SO₄. The solventwas then removed by evaporation under reduced pressure and the residuethus obtained (20 g) was purified by flash chromatography, eluting witha 7/3 hexane/ethyl acetate mixture.

The product obtained was converted into the corresponding hydrochlorideby dissolving in ethyl acetate, adding hydrochloric ethanol andcrystallizing from a 9/1 mixture of ethyl acetate/absolute ethanol.

The desired product (12.8 g) was thus obtained.

m.p.: 201-202° C. (dec.)

Elemental analysis

For C₂₅H₃₁N₅O₂.HCl

C H N Found % 63.83 6.74 14.75 Calculated % 63.89 6.86 14.90

¹H-NMR (δ, DMSO-d₆): 1.55 (d, J=7 Hz, 6H); 1.50-2.10 (m, 5H); 3.00-3.70(m, 6H); 4.16 (s, 2H); 5.08 (septet, J=7 Hz, 1H); 7.11 (t, J=7 Hz, 1H);7.20-7.50 (m, 4H); 7.66 (d, J=8 Hz, 2H); 7.79 (d, J=8 Hz, 1H);8.18 (d,J=8 Hz, 1H); 8.37 (t, J=6 Hz, 1H); 10.03 (broad s, 1H); 11.04 (s, 1H).

EXAMPLE 3N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1H-indazole-3-carboxamidetosylate (AF3R276) (Compound I: R1=R2=R3=R4=R5=R6=R7=R8=H, X═C(O)NH)

A solution of the product prepared as described in Example 1b) (5.7 g;0.026 mol) in dichloromethane (30 ml) was added, via a dropping funnel,to a suspension of7H,14H-indazolo[2′,3′:4,5]pyrazino[1,2-b]indazole-7,14-dione (3.7 g;0.013 mol), prepared as described in J.O.C. 1958, Vol. 23, p. 621, intoluene (30 ml).

After stirring at room temperature for 18 hours, the reaction mixturewas transferred into a separating funnel. Dichloromethane (30 ml) wasadded and the organic phase was washed with 1N NaOH. The organic phasewas separated out and dried over Na₂SO₄. The solvent was then removed byevaporation under reduced pressure and the product thus obtained wasconverted into the corresponding tosylate by dissolving in ethylacetate, adding a stoichiometric amount of p-toluenesulphonic acid andrecrystallizing from 95° ethanol.

The desired product (4.3 g) was thus obtained.

m.p.: 215.5-217.5° C.

Elemental analysis

For C₂₂H₂₅N₅O₂.C₇H₈O₃S-1/2H₂O

C H N Found % 60.71 5.92 12.24 Calculated % 60.82 5.98 12.23

¹H-NMR (δ, DMSO-d₆): 1.48-1.73 (m, 2H); 1.77-2.10 (m, 3H); 2.28 (s, 3H);2.93-3.65 (m, 6H); 4.10 (s, 2H); 7.07-7.67 (m, 12H); 8.18 (d, J=8 Hz,1H); 8.53 (t, J=6 Hz, 1H); 9.63 (broad s, 1H); 10.52 (s, 1H); 13.57 (s,1H).

EXAMPLE 4N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1-benzyl-1H-indazole-3-carboxamidehydrochloride (AF3R277) (Compound I: R1=R3=R4=R5=R6=R7=R8=H, R2=C₆H₅CH₂,X═C(O)NH)

-   a) 1-benzyl-1H-indazole-3-carboxyl chloride

Thionyl chloride (5.6 ml; 0.077 mol) was added to a suspension of1-benzyl-1H-indazole-3-carboxylic acid (6.5 g; 0.026 mol), prepared asdescribed in J. Med. Chem., 1976, Vol. 19 (6), pp. 778-783, in toluene(65 ml), and the reaction mixture was refluxed for 2 hours. The solventwas removed by evaporation under reduced pressure and the residue wastaken up twice with toluene (2×50 ml) to give the desired product (7 g),which was used without further purification.

-   b)    N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1-benzyl-1H-indazole-3-carboxamide    hydrochloride

By working in a manner similar to that described in Example 2, theproduct prepared as described in Example 4a) (8.2 g; 0.030 mol) wasreacted with the product as described in Example 1b) (7.5 g; 0.030 mol)and the reaction product was converted into the correspondinghydrochloride.

The desired product (4.5 g) was thus obtained.

m.p.: 196-198° C.

Elemental analysis

For C₂₉H₃₁N₅O₂.HCl.1/2H₂O

C H N Found % 66.19 6.28 13.24 Calculated % 66.09 6.31 13.29

¹H-NMR (δ, CDCl₃): 1.64-2.40 (m, 5H); 3.10-3.77 (m, 6H); 4.13 (s, 2H);5.58 (s, 1H); 7.00-7.40 (m, 13H); 7.74 (d, J=8 Hz, 1H); 8.34 (d, J=8 Hz,1H); 10.88 (s, 1H); 11.26 (broad s, 1H).

EXAMPLE 5N3-((1-(2-oxo2-((4-((phenylmethyl)oxy)phenyl)amino)ethyl)-4-piperidy)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide(AF3R331) (Compound I: R1=R4=R5=R6=R7=R8=H, R2=i-C₃H₇, R3=4-OCH₂C₆H₅,X═C(O)NH)

-   a)    N1-(4-((phenylmethyl)oxy)phenyl)-2-(4-(aminomethyl)-1-piperidyl)ethanamide    hydrochloride

The product prepared as described in Example 1a) (68 g; 0.34 mol) wasreacted with N1-(4-((phenylmethyl)oxy)phenyl)-2-chloroethanamide (93.7g; 0.34 mol), prepared as described in Indian J. Appl. Chem. 1967, Vol.30(3-4), pp. 91-95, working in a manner similar to that described inExample 1b).

The oily residue (120 g) thus obtained was purified by flashchromatography, eluting with a 10/4/1 chloroform/methanol/aqueousammonia mixture.

N1-(4-((Phenylmethyl)oxy)phenyl)-2-(4-(aminomethyl)-1-piperidyl)ethanamidebase (70 g) was thus obtained, which was converted into thecorresponding dihydrochloride by dissolving in ethanol, addinghydrochloric ethanol and recrystallizing from absolute ethanol to give65 g of the desired product.

Elemental analysis:

For C₂₁H₂₇N₃O₂.2HCl

C H N Found % 58.88 6.75 9.55 Calculated % 59.16 6.86 9.85

¹H-NMR (δ, DMSO-d₆): 1.45-1.70 (m, 2H); 1.70-2.20 (m, 3H); 2.72 (s, 2H);3.02-3.68 (m, 4H); 4.12 (s, 2H); 5.08 (s, 2H); 7.00 (d, J=9 Hz, 2H);7.26-7.48 (m, 5H); 8.56 (d, J=9 Hz, 2H); 8.27 (s, 3H); 10.14 (s, 1H);10.92 (s, 1H).

-   b)    N3-((1-(2-oxo-2-((4-((phenylmethyl)oxy)phenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide

1-(1-Methylethyl)-1H-indazole-3-carboxyl chloride (31.1 g; 0.14 mol),prepared as described in EP-A-0 975 623, was added portionwise to asuspension ofN1-(4-((phenylmethyl)oxy)phenyl)-2-(4-(aminomethyl)-1-piperidyl)ethanamide,prepared as described in Example 5a) (49.5 g; 0.14 mol), in toluene (500ml).

The reaction mixture was stirred at room temperature for 6 hours andthen filtered. The solid thus obtained was taken up in 2N NaOH anddichloromethane. The mixture was transferred into a separating funnel.The organic phase was separated out and dried over Na₂SO₄. The solventwas removed by evaporation under reduced pressure and the residue thusobtained (75 g) was crystallized twice from isopropanol to give 56 g ofthe desired product.

m.p.: 113-115° C.

Elemental analysis

For C₃₂H₃₇N₅O₃

C H N Found % 71.03 7.19 12.95 Calculated % 71.22 6.91 12.98

¹H-NMR (δ, DMSO-d₆): 1.24-1.44 (m, 2H); 1.54 (d, J=7 Hz, 6H); 1.48-1.78(m, 3H); 2.10 (t, J=11 Hz, 2H); 2.87 (d, J=11 Hz, 2H); 3.05 (s, 2H);3.24 (t, J=6 Hz, 2H); 5.07 (septet, J=7 Hz, 1H); 5.07 (s, 2H); 6.96 (d,J=9 Hz, 2H); 7.20-7.48 (m, 7H); 7.54 (d, J=9 Hz, 2H); 7.78 (d, J=9 Hz,1H); 8.19 (d, J=8 Hz, 1H); 8.23 (t, J=6 Hz, 1H); 9.52 (s, 1H).

EXAMPLE 6N3-((1-(2-((4-hydroxyphenyl)amino)-2-oxoethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamidehydrochloride (AF3R278) (Compound I: R1=R4=R5=R6=R7=R8=H, R2=i-C₃H₇,R3=4-OH, X═C(O)NH)

A solution of the product prepared as described in Example 5 (36.5 g;0.068 mol) in 95° ethanol (1000 ml) was hydrogenated over 10% Pd—C (3.65g) at 40 psi for 5 hours. The reaction mixture was then filtered and thefiltrate was concentrated under reduced pressure.

The product thus obtained was converted into the correspondinghydrochloride by dissolving in absolute ethanol, adding hydrochloricethanol and recrystallizing from absolute ethanol, to give 20 g of thedesired product.

m.p.: 277° C. (dec.)

Elemental analysis

For C₂₅H₃₁N₅O₃.HCl

C H N Found % 61.76 6.76 14.44 Calculated % 61.78 6.64 14.41

¹H-NMR (δ, DMSO-d₆): 1.55 (d, J=7 Hz, 6H); 1.46-1.75 (m, 2H); 1.75-2.10(m, 3H); 2:95-3.64 (m, 6H); 4.07 (s, 2H); 5.08 (septet, J=7 Hz, 1H);6.75 (d, J=9 Hz, 2H); 7.20-7.31 (m, 1H); 7.35-7.49 (m, 3H); 7.79 (d, J=9Hz, 1H); 8.17 (dt, J=8;1 Hz, 1H); 8.36 (t, J=6 Hz, 1H); 9.37 (s, 1H);9.89 (broad s, 1H); 10.62 (s, 1H).

EXAMPLE 7N3-((1-(2-oxo-2-((4-nitrophenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide(AF3R335) (Compound I: R1=R4=R5=R6=R7=R8=H, R2=i-C₃H₇, R3=4-NO₂,X═C(O)NH)

-   a) 2-(4-(aminomethyl)-1-piperidyl)-N-(4-nitrophenyl)acetamide

The product prepared as described in Example 1a) (28 g; 0.14 mol) wasreacted with N1-(4-nitrophenyl)-2chloroethanamide (30 g; 0.14 mol),working in a manner similar to that described in Example 1b).

An oily residue (20 g) was thus obtained, and was purified by flashchromatography, eluting with a 10/4/1 chloroform/methanol/aqueousammonia mixture to give 15 g of the desired product.

Elemental analysis

For C₁₄H₂₀N₄O₃

C H N Found % 57.23 7.00 18.98 Calculated % 57.52 6.90 19.16

¹H-NMR (δ, DMSO-d₆+D₂O): 1.20-1.40 (m, 2H); 1.48-1.78 (m, 3H); 2.17 (t,J=12 Hz, 2H); 2.72 (d, J=7 Hz, 2H); 2.89 (d, J=12 Hz, 2H); 3.21 (s, 2H);7.90 (d, J=9 Hz, 2H); 8.23 (d, J=9 Hz, 2H).

-   b)    N3-((1-(2-oxo-2-((4-nitrophenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide

1-(1-Methylethyl)-1H-indazole-3-carboxyl chloride (3.1 g; 0.013 mol),prepared as described in EP-A-0 975 623, was added portionwise to asuspension of the product prepared according to Example 7a) (4.07 g,0.014 mol) in toluene (300 ml).

The reaction mixture was stirred at room temperature for 6 hours. Thesolvent was then removed by evaporation under reduced pressure. Theresidue was taken up in 1N NaOH and dichloromethane. The mixture wastransferred into a separating funnel. The organic phase was separatedout and dried over Na₂SO₄. The solvent was removed by evaporation underreduced pressure. The residue thus obtained was purified by flashchromatography, eluting with ethyl acetate, to give 2.8 g of the desiredproduct.

Elemental analysis

For C₂₅H₃₀N₆O₄

C H N Found % 62.62 6.38 17.33 Calculated % 62.75 6.32 17.56

¹H-NMR (δ, CDCl₃): 1.36-1.55 (m, 2H); 1.61 (d, J=7 Hz, 6H); 1.66-1.98(m, 3H); 2.32 (td, J=12;2 Hz, 2H); 2.95 (d, J=12 Hz, 2H); 3.13 (s, 2H);3.46 (t, J=7 Hz, 2H); 4.89 (septet, J=7 Hz, 1H); 7.19 (t, J=6 Hz, 1H);7.23-7.30 (m, 1H); 7.35-7.50 (m, 2H); 7.75 (d, J=9 Hz, 2H); 8.21 (d, J=9Hz, 2H); 8.38 (dt, J=8;1 Hz, 1H); 9.60 (s, 1H).

EXAMPLE 85-methyl-N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1H-indazole-3-carboxamidehydrochloride (AF3R295) (Compound I: R1=CH₃, R2=R3=R4=R5=R6=R7=R8=H,X═C(O)NH)

-   a)    2,9-dimethyl-7H,14H-indazolo[2′,3′:4,5]pyrazino[1,2-b]indazole-7,14-dione

Thionyl chloride (11 ml; 0.151 mol) was added to a suspension of5-methyl-1H-indazole-3-carboxylic acid (12.2 g; 0.056 mol), prepared asdescribed in J. Heterocyclic Chem. 1964, Vol. 1 (5) 239-241, in toluene(130 ml), and the reaction mixture was refluxed for 4 hours. The solventwas removed by evaporation under reduced pressure and the residue wastaken up twice in toluene to give 12 g of the desired product.

¹H-NMR (δ, CDCl₃): 2.54 (d, J=1 Hz, 6H); 7.35 (dd, J=9;2 Hz, 2H); 7.85(d, J=9 Hz, 2H); 8.01 (m, 1H).

-   b)    5-methyl-N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1H-indazole-3-carboxamide    hydrochloride

The product prepared according to Example 1b) (4.5 g; 0.018 mol) and theproduct, prepared according to Example 8a) (2.8 g; 0.009 mol) werereacted in a manner similar to that described in Example 3.

3.8 g of5-methyl-N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1H-indazole-3-carboxamidewere thus obtained, and were converted into the correspondinghydrochloride by dissolving in ethyl acetate, adding hydrochloricethanol and recrystallizing from a 95/5 ethyl acetate/ethanol mixture togive 2.7 g of the desired product.

m.p.: 252° C. (dec.)

Elemental analysis

For C₂₃H₂₇N₅O₂.HCl

C H N Found % 62.62 6.38 15.70 Calculated % 62.51 6.39 15.85

¹H-NMR (δ, DMSO-d₆): 1.50-1.72 (m, 2H); 1.80-2.00 (m, 3H); 2.43 (s, 3H);2.96-3.64 (m, 6H); 4.13 (s, 2H); 7.12 (t, J=7 Hz, 1H); 7.24 (dd J=9;1.5Hz, 1H); 7.36 (t, J=7 Hz, 2H); 7.50 (d, J=9 Hz, 1H); 7.62 (d, J=7 Hz,2H); 7.95 (s, 1H); 8.46 (t, J=6 Hz, 1H); 9.86 (broad s, 1H); 10.52 (s,1H); 13.51 (s, 1H).

EXAMPLE 95-methyl-N3-((1-(2oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-l-(1-methylethyl)-1H-indazole-3-carboxamide hydrochloride (AF3R299)(Compound I: R1=CH₃, R2=i-C₃H₇, R3=R4=R5=R6=R7=R8=H, X═C(O)NH)

-   a) isopropyl 1-(1-methylethyl)-5-methyl-1H-indazole-3-carboxylate

A 60% suspension of sodium hydride in mineral oil (17.1 g; 0.43 mol) wasadded to a suspension of 5-methyl-1H-indazole-3-carboxylic acid (30 g;0.17 mol), prepared as described in J. Heterocyclic Chem. 1964, Vol. 1(5) 239-241, in dimethylformamide (450 ml), and the reaction mixture washeated to 70° C. After 30 minutes, isopropyl bromide (48 ml, 0.51 mol)was added.

The reaction mixture was stirred for 6 hours at 70° C. After cooling,water was added. The reaction mixture was transferred into a separatingfunnel and extracted with diethyl ether. The organic phase was washedwith saturated sodium bicarbonate solution and the solvent was finallyremoved by evaporation under reduced pressure.

20 g of an oil were thus obtained, and were purified by flashchromatography, eluting with a 7/3 hexane/ethyl acetate mixture, to give12 g of the desired product.

¹H-NMR (δ, CDCl₃): 1.47 (d, J=6 Hz, 6H); 1.64 (d, J=7 Hz, 6H); 2.50 (d,J=1 Hz, 3H); 4.92 (septet, J=7 Hz, 1H); 5.39 (septet, J=6 Hz, 1H); 7.23(dd, J=9;1 Hz, 1H); 7.40 (d, J=9 Hz, 1H); 7.95 (quintet, J=1 Hz, 1H).

-   b) 1-(1-methylethyl)-5-methyl-1H-indazole-3-carboxylic acid

A suspension of the product prepared according to Example 9a) (8 g, 0.03mol) in 1M NaOH (42 ml) was refluxed for 3 hours. It was then pouredinto water, acidified with 2M HCl and extracted with dichloromethane.After evaporating off the solvent under reduced pressure, 7 g of thedesired product were obtained.

¹H-NMR (δ, CDCl₃): 1.61 (d, J=7 Hz, 6H); 2.44 (s, 3H); 4.88 (septet, J=7Hz, 1H); 7.19 (d, J=9 Hz, 1H); 7.34 (d, J=9 Hz, 1H); 7.97 (s, 1H); 9.32(broad s, 1H).

-   c) 1-(1-methylethyl)-5-methyl-1H-indazole-3-carboxyl chloride

The product prepared according to Example 9a) (12.2 g; 0.056 mol) waschlorinated in a manner similar to that described in Example 4a).

13.3 g of the desired product were thus obtained, and were used withoutfurther purification.

-   d)    5-methyl-N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide    hydrochloride

The product prepared according to Example 1b) (3 g; 0.012 mol) was addedto a suspension of the product prepared according to Example 9c) (2.9 g;0.012 mol) in toluene (60 ml).

The reaction mixture was stirred at room temperature for 6 hours and thesolvent was then removed under reduced pressure. The residue was takenup in 2N NaOH and dichloromethane. The mixture was transferred into aseparating funnel. The organic phase was separated out and dried overNa₂SO₄. The solvent was removed by evaporation under reduced pressure.The residue thus obtained (4 g) was purified by flash chromatography,eluting with a 97/3 chloroform/methanol mixture. The product obtainedwas converted into the corresponding hydrochloride by dissolving inethyl acetate, adding hydrochloric ethanol and crystallizing fromabsolute ethanol, to give 2.3 g of the desired product.

m.p.: 241° C. (dec.)

Elemental analysis

For C₂₆H₃₃N₅O₂.HCl

C H N Found % 64.69 7.09 14.44 Calculated % 64.52 7.08 14.47

¹H-NMR (δ, DMSO-d₆): 1.59 (d, J=7 Hz, 6H); 1.78-2.25 (m, 5H); 2.47 (s,3H); 3.06-3.27 (m, 2H); 3.41 (t, J=6 Hz, 2H); 3.56-3.77 (m, 2H); 4.01(s, 2H); 4.83 (septet, J=7 Hz, 1H); 7.06-7.39 (m, 6H); 7.76 (d, J=8 Hz,2H); 8.12 (s, 1H); 10.91 (s, 1H); 11.79 (broad s, 1H).

EXAMPLE 10N3-((1-(2-oxo-2-((4-(dimethylamino)phenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamidedihydrochloride (AF3R301) (Compound I: R1=R4=R5=R6=R7=R8=H, R2=i-C₃H₇,R₃=4-N(CH₃)₂, X═C(O)NH)

-   a)    2-(4-(aminomethyl)-1-piperidyl)-N-(4-(dimethylamino)phenyl)-acetamide

The product prepared according to Example 1a) (25 g; 0.12 mol) wasreacted with N1-(4-(dimethylamino)phenyl)-2-chloroethanamide (25.5 g;0.12 mol) in a manner similar to that described in Example 1b).

36 g of an oily residue were obtained, and were purified by flashchromatography, eluting with a 10/4/1 chloroform/methanol/aqueousammonia mixture to give 25 g of the desired product.

Elemental analysis:

For C₁₆H₂₆N₄O

C H N Found % 66.53 9.30 18.97 Calculated % 66.17 9.02 19.29

¹H-NMR (δ, DMSO-d₆+D₂O): 1.18-1.50 (m, 2H); 1.55-1.78 (m, 3H); 2.15-2.35(m, 2H); 2.80-3.10 (m, 10H); 3.34 (s, 2H); 6.67 (d, J=9 Hz, 2H); 7.39(d, J=9 Hz, 2H).

-   b)    N3-((1-(2-oxo-2-((4-dimethylamino)phenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide    dihydrochloride

By working in a manner similar to that described in Example 2, theproduct prepared according to Example 10a) (6.4 g; 0.022 mol) wasreacted with 1-(1-methylethyl)-1H-indazole-3-carboxyl chloride (4.9 g;0.022 mol) and the reaction product was converted into the correspondinghydrochloride. 4.2 g of the desired product were thus obtained.

m.p.: 203° C. (dec.)

Elemental analysis

For C₂₆H₃₆N₆O₂.2HCl.H₂O

C H N Found % 57.18 7.17 14.68 Calculated % 57.14 7.10 14.81

¹H-NMR (δ, CDCl₃): 1.61 (d, J=7 Hz, 6H); 1.78-2.30 (m, 5H); 3.16 (s,6H); 3.00-3.90 (m, 6H); 4.31 (s, 2H); 4.90 (septet, J=7 Hz, 1H); 7.25(t, J=8 Hz, 1H); 7.35-7.46 (m, 2H); 7.49 (d, J=9 Hz, 1H); 7.70 (d, J=9Hz, 2H); 7.86 (d, J=9 Hz, 2H); 8.30 (d, J=8 Hz, 1H); 10.65 (broad s,2H); 11.55 (s, 1H).

EXAMPLE 11N3-((1-(2-oxo-2-((2,6-dimethylphenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamideoxalate (AF3R305) (Compound I: R1=R5=R6=R7=R8=H, R2=i-C₃H₇, R3=2-CH₃,R4=6-CH₃, X═C(O)NH)

-   a) 2-(4-(aminomethyl)-1-piperidyl)-N-(2,6-dimethylphenyl)acetamide    dihydrochloride

The product prepared according to Example 1a) (32 g; 0.16 mol) wasreacted with N1-(2,6-dimethylphenyl)-2-chloroethanamide (31.6 g; 0.16mol) in a manner similar to that described in Example 1b).

54 g of a residue were thus obtained, and were crystallized from ethylacetate to give 45 g of the desired product, which was converted intothe corresponding hydrochloride by dissolving in ethyl acetate, addinghydrochloric ethanol and recrystallizing from 95° ethanol to give 40 gof the desired product.

Elemental analysis

For C₁₆H₂₅N₃O.2HCl

C H N Found % 55.12 7.77 20.22 Calculated % 55.17 7.81 20.36

¹H-NMR (δ, DMSO-d₆): 1.43-1.71 (m, 2H); 1.73-2.06 (m, 3H); 2.18 (s, 6H);2.71 (s, 2H); 3.05-3.66 (m, 4H); 4.25(s, 2H); 7.10 (s, 3H); 8.35 (broads, 3H); 10.19 (broad s, 1H); 10.33 (s, 1H).

-   b)    N3-((1-(2-oxo-2-((2.6-dimethylphenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide    oxalate

1-(1-Methylethyl)-1H-indazole-3-carboxyl chloride (11.3 g; 0.051 mol),prepared as described in EP-A-0 975 623, was added portionwise to asuspension of the product prepared as described in Example 11a), as base(14.1 g; 0.051 mol), in toluene (200 ml).

The reaction mixture was stirred at room temperature for 6 hours. Afterremoving the solvent by evaporation under reduced pressure, the residuewas taken up in 1N NaOH and dichloromethane. The mixture was transferredinto a separating funnel. The organic phase was separated out and driedover Na₂SO₄. The solvent was removed by evaporation under reducedpressure. The residue thus obtained (20 g) was purified by flashchromatography, eluting with ethyl acetate. The product obtained wasconverted into the corresponding oxalate by dissolving in ethyl acetate,adding a stoichiometric amount of oxalic acid and crystallizing from 950ethanol, to give 7.8 g of the desired product.

m.p.: 214° C. (dec.)

Elemental analysis

For C₂₇H₃₅N₅O₂.C₂H₂O₄

C H N Found % 63.09 6.80 12.73 Calculated % 63.14 6.76 12.70

¹H-NMR (δ, DMSO-d₆): 1.54 (d, J=7 Hz, 6H); 1.42-1.64 (m, 2H); 1.72-1.92(m, 3H); 2.15 (s, 6H); 2.78 (t, J=12 Hz, 2H); 3.17-3.40 (m, 4H); 3.81(s, 2H); 5.08 (septet, J=7 Hz, 1H); 6.20 (broad s, 2H); 7.09 (s, 3H);7.20-7.30 (m, 1H); 7.38-7.48 (m, 1H); 7.79 (d, J=9Hz, 1H); 8.17 (d, J=8Hz, 1H); 8.31 (t, J=6 Hz, 1H); 9.68 (s, 1H).

EXAMPLE 12N3-((2-(2-oxo-2-((4-aminophenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamidedihydrochloride (AF3R292) (Compound I: R1=R4=R5=R6=R7=R8=H, R2=i-C₃H₇,R3=4-NH₂, X═C(O)NH)

A solution of the product prepared according to Example 7b) (1.4 g;0.003 mol) in absolute ethanol (50 ml) was hydrogenated over 10% Pd—C(90 mg) at 40 psi for 3 hours. The mixture was then filtered and thefiltrate was concentrated under reduced pressure. The product thusobtained was converted into the corresponding dihydrochloride bydissolving in ethyl acetate, adding hydrochloric ethanol andcrystallizing from a 95/5 ethyl acetate/ethanol mixture, to give 0.7 gof the desired product.

m.p.: 252° C. (dec.)

Elemental analysis

For C₂₅H₃₂N₆O₂.2HCl.H₂O

C H N Found % 55.70 6.52 15.44 Calculated % 55.66 6.73 15.58

¹H-NMR (δ, DMSO-d₆): 1.55 (d, J=7 Hz, 6H); 1.40-2.09 (m, 5H); 2.96-3.71(m, 6H); 4.16 (s, 2H); 5.00 (septet, J=7 Hz, 1H); 7.20-7.38 (m, 3H)7.30-7.48 (m, 1H); 7.70 (d, J=9 Hz, 2H); 7.79 (d, J=9 Hz, 2H); 8.17 (d,J=8 Hz, 1H); 8.37 (t, J=6 Hz, 1H); 10.03 (broad s, 4H); 11.17 (s, 1H).

TESTS

1. CFA-Induced Mechanical Hyperalgesia in Rats

Male CD rats weighing 150-200 g on arrival were used.

By means of an analgesimeter, rats with a response threshold to amechanical nociceptive stimulus in the range from 150 to 180 g wereselected. By applying a gradual increase in pressure onto the dorsalregion of the left hind paw of the rat, the instrument makes it possibleto record the nocifensive response, expressed in grams, corresponding tothe moment at which the animal retracts the paw [Randall L O and SelittoJ J. A method for the measurement of analgesic activity on inflamedtissue. Arch. lnt. Pharmacodyn. Ther. 1957; 111: 409-419].

The hyperalgesia was induced by unilateral injection of 150 μl of“Complete Freund's Adjuvant” (CFA) into the surface of the left hind pawof the animal [Andrew D, Greenspan J D. Mechanical and heatsensitization of cutaneous nociceptors after peripheral inflammation inthe rat. J Neurophysiol. 1999; 82(5): 2649-2656; Hargreaves K, Dubner R,Brown R, Flores C, Joris J. A new and sensitive method for measuringthermal nociception in cutaneous hyperalgesia. Pain 1988; 32: 77-88].

The test compounds were tested (dose: 10⁻⁵ mol/kg) by performing thetest 23 hours after injecting the CFA.

One hour after the treatment, the pain threshold measured in controlanimals was compared with that measured in animals treated with the testproduct. The control animals were treated with the same vehicle (water)used for administering the test products. The results are illustrated inTable 1.

TABLE 1 Effect on CFA Pain threshold (g) Treatment No. of rats 1 h afterthe treatment Vehicle 12 120 ± 6.1 AF3R172 12 175 ± 10.2 AF3R278 12 164± 10.2 AF3R301 12 151 ± 10.7 AF3R276 12 185 ± 15.9 AF3R277 12 170 ± 10.7AF3R295 12 202 ± 17.0 AF3R299 12 167 ± 8.5 AF3R305 12 174 ± 8.4 AF3R29212 154 ± 11.5 AF3R331 12 156 ± 8.7 AF3R335 12 168 ± 6.8 Pain thresholdof normal animals of equivalent weight/age = 155 ± 2.1 g2. Mechanical Hyperalgesia in Rats with Streptozotocin-Induced Diabetes

Male CD rats weighing 240-300 g on arrival were used. The diabeticsyndrome was induced by means of a single intraperitoneal (i.p.)injection of 80 mg/kg of streptozotocin dissolved in sterilephysiological solution [Courteix C, Eschalier A, Lavarenne J.Streptozotocin-induced diabetic rats: behavioural evidence for a modelof chronic pain. Pain, 1993; 53: 81-88; Bannon A W, Decker M W, Kim D J,Campbell J E, Arneric S P. ABT-594, a novel cholinergic channelmodulator, is efficacious in nerve ligation and diabetic neuropathymodels of neuropathic pain. Brain Res. 1998; 801:158-63].

At least three weeks after the injection of streptozotocin, rats with alevel of glycemia ≧300 mg/dl and with a response threshold to amechanical nociceptive stimulus ≦120 g were selected. The glycemialevels were measured by means of a reflectometer, using reactive stripsimpregnated with glucose oxidase. The pain threshold was measured usingan analgesimeter. By applying a gradual increase in pressure onto thedorsal area of the left hind paw of the rat, the instrument makes itpossible to record the nocifensive response, expressed in grams,corresponding to the moment at which the animal retracts the paw.

Two hours after the treatment, the pain threshold measured in controlanimals was compared with that measured in animals treated with the testproduct (dose: 10⁻⁵ mol/kg).

The control animals were treated with the same vehicle (water) used foradministering the test products. The results are illustrated in Table 2.

TABLE 2 Effect on diabetic neuropathy Pain threshold (g) Treatment No.of rats 2 h after the treatment Vehicle 8 114 ± 2.7 AF3R172 8 186 ± 13.0AF3R278 8 240 ± 16.5 AF3R301 8 201 ± 13.8 AF3R276 8 210 ± 10.9 AF3R277 8188 ± 11.0 AF3R295 8 212 ± 14.6 AF3R299 8 200 ± 10.7 AF3R305 8 189 ± 9.2AF3R292 8 202 ± 8.7 AF3R331 8 192 ± 11.5 AF3R335 8 180 ± 13.0 Painthreshold of normal animals of equivalent weight/age = 240 ± 8.7 g

1. An indazolamide of formula I:

wherein X is an NHC(O) or C(O)NH group, R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino, sulphonylmethyl, aminosulphonylmethyl, linear or branched C₁₋₃ alkyl or C₁₋₃ alkoxy group, R2 is a hydrogen atom or a linear or branched C₁₋₆ alkyl group or an aryl(C₁₋₃)alkyl group in which the abovementioned groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, C₁₋₃ alkyl and C₁₋₃ alkoxy, R3 and R4, which may be identical or different, are a hydrogen or halogen atom, or an amino, nitro, hydroxyl, linear or branched C₁₋₃ alkyl, C₁₋₃ alkoxy, di(C₁₋₃)alkylamino, acetylamino or O—(C₁₋₃)alkylphenyl group, or R3 and R4, together, form a 5- to 7-membered ring in which one or two of the said members may be a hetero atom selected from the group consisting of N, S and O, R5, R6, R7 and R8, which may be identical or different, are H or methyl; and acid-addition salts thereof with pharmaceutically acceptable organic and mineral acids.
 2. An indazolamide according to claim 1, wherein R1 is H, methyl or methoxy.
 3. An indazolamide according to claim 1, wherein R2 is H, methyl or isopropyl.
 4. An indazolamide according to claim 1, wherein R3 is H, methyl, hydroxyl, amino or dimethylamino.
 5. An indazolamide according to claim 1, wherein R4 is H, methyl or hydroxyl.
 6. An indazolamide according to claim 1, wherein R5, R6, R7 and R8 are H.
 7. An indazolamide according to claim 1, wherein it is a salt of addition of a pharmaceutically acceptable acid selected from the group consisting of oxalic acid, maleic acid, succinic acid, citric acid, tartaric acid, lactic acid, methanesulphonic acid, para-toluenesulphonic acid, hydrochloric acid, phosphoric acid and sulphuric acid.
 8. N3-((1-(2-Oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)- 1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 9. A hydrochloride salt of the compound of claim
 8. 10. N3-((1-(2-Oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 11. A tosylate salt of the compound of claim
 10. 12. N3-((1-(2-Oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1-benzyl-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 13. A hydrochloride salt of the compound of claim
 12. 14. N3-((1-(2-Oxo-2-((4-((phenylmethyl)oxy)phenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 15. N3-((1-(2-((4-Hydroxyphenyl)amino)-2-oxoethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 16. A hydrochloride salt of the compound of claim
 15. 17. N3-((1-(2-Oxo-2-((4-nitrophenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 18. N3-((1-(2-Oxo-2-((4-aminophenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 19. A dihydrochloride salt of the compound of claim
 18. 20. 5-Methyl-N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 21. A hydrochloride salt of the compound of claim
 20. 22. 5-Methyl-N3-((1-(2-oxo-2-(phenylamino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 23. A hydrochloride salt of the compound of claim
 22. 24. N3-((1-(2-Oxo-2-((4-(dimethylamino)phenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof.
 25. A dihydrochloride salt of the compound of claim
 24. 26. N3-((1-(2-Oxo-2-((2,6-dimethylphenyl)amino)ethyl)-4-piperidyl)methyl)-1-(1-methylethyl)-1H-indazole-3-carboxamide and pharmaceutically acceptable acid-addition salts thereof
 27. An oxalate salt of the compound of claim
 26. 28. A process for preparing an indazolamide of formula I:

wherein X is an NHC(O) or C(O)NH group, R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino, sulphonylmethyl, aminosulphonylmethyl, linear or branched C₁₋₃ alkyl or C₁₋₃ alkoxy group, R2 is a hydrogen atom or a linear or branched C₁₋₆ alkyl group or an aryl(C₁₋₃)alkyl group in which the abovementioned groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, C₁₋₃ alkyl and C₁₋₃ alkoxy, R3 and R4, which may be identical or different, are a hydrogen or halogen atom, or an amino, nitro, hydroxyl, linear or branched C₁₋₃ alkyl, C₁₋₃ alkoxy, di(C₁₋₃)alkylamino, acetylamino or O—(C₁₋₃)alkylphenyl group, or R3 and R4, together, form a 5- to 7-membered ring in which one or two of the said members may be a hetero atom selected from the group consisting of N, S and O, R5, R6, R7 and R8, which may be identical or different, are H or methyl; and acid-addition salts thereof with pharmaceutically acceptable organic and mineral acids, wherein it comprises the following stages: a) condensing an amine of formula (II)

in which X, R3, R4, R5, R6, R7 and R8 have the meanings given above, with an indazolecarboxylic acid derivative of formula (IIIa)

in which R1 and R2 have the meanings given above, and Y is a chlorine or bromine atom, or a group OR or OC(O)R, in which R is an alkyl with a linear or branched chain comprising from 1 to 6 carbon atoms, or of formula (IIIb)

in which R1 has the meanings given above, to give the indazolamide of formula (I), and b) optionally, forming an acid-addition salt of the indazolamide of formula (I) with a pharmaceutically acceptable organic or mineral acid.
 29. The process according to claim 28, wherein stage (a) is performed by reacting a compound of formula (II) with a compound of formula (IIIa) in which Y is chlorine or with a compound of formula (IIIb) in the presence of a suitable diluent at a temperature in the range between 0 and 140° C. for a time of between 0.5 and 20 hours.
 30. The process according to claim 29, wherein the reaction temperature is in the range between 15 and 40° C.
 31. The process according to claim 29, wherein the reaction time ranges from 1 to 14 hours.
 32. The process according to claim 29, wherein the diluent is aprotic.
 33. The process according to claim 32, wherein the diluent is an aprotic apolar diluent.
 34. The process according to claim 9, wherein when Y is chlorine or bromine, the abovementioned stage a) is performed in the presence of an organic or mineral acid acceptor.
 35. A pharmaceutical composition containing an effective amount of a compound of formula (I):

wherein X is an NHC(O) or C(O)NH group, R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino, sulphonylmethyl, aminosulphonylmethyl, linear or branched C₁₋₃ alkyl or C₁₋₃ alkoxy group, R2 is a hydrogen atom or a linear or branched C₁₋₆ alkyl group or an aryl(C₁₋₃)alkyl group in which the abovementioned groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, C₁₋₃ alkyl and C₁₋₃ alkoxy, R3 and R4, which may be identical or different, are a hydrogen or halogen atom, or an amino, nitro, hydroxyl, linear or branched C₁₋₃ alkyl, C₁₋₃ alkoxy, di(C₁₋₃)alkylamino, acetylamino or O-(C₁₋₃)alkylphenyl group, or R3 and R4, together, form a 5- to 7-membered ring in which one or two of the said members may be a hetero atom selected from the group consisting of N, S and O, R5, R6, R7 and R8, which may be identical or different, are H or methyl; or of an acid-addition salt thereof with a pharmaceutically acceptable acid, and at least one pharmaceutically acceptable inert ingredient.
 36. A method of treating chronic pain in a subject in need thereof comprising administering to said subject an indazolamide of formula I:

wherein X is an NHC(O) or C(O)NH group, R1 is a hydrogen or halogen atom, or an aminocarbonyl, acetylamino, sulphonylmethyl, aminosulphonylmethyl, linear or branched C₁₋₃ alkyl or C₁₋₃ alkoxy group, R2 is a hydrogen atom or a linear or branched C₁₋₆ alkyl group or an aryl(C₁₋₃)alkyl group in which the abovementioned groups are optionally substituted with one or more substituents selected from the group consisting of halogen atoms, C₁₋₃ alkyl and C₁₋₃ alkoxy, R3 and R4, which may be identical or different, are a hydrogen or halogen atom, or an amino, nitro, hydroxyl, linear or branched C₁₋₃ alkyl, C₁₋₃ alkoxy, di(C₁₋₃)alkylamino, acetylamino or O-(C₁₋₃)alkylphenyl group, or R3 and R4, together, form a 5- to 7-membered ring in which one or two of the said members may be a hetero atom selected from the group consisting of N, S and O, R5, R6, R7 and R8, which may be identical or different, are H or methyl; and acid-addition salts thereof with pharmaceutically acceptable organic and mineral acids.
 37. The method according to claim 36, wherein said chronic pain is a disorder selected from the group consisting of rheumatoid arthritis, osteoarthritis, fibromyalgia, oncology pain, and neuropathic pain. 